Field of the Invention
The present invention is related to methods of impairing progenitor hematologic cancer cells or treating hematologic cancer by targeting a cell surface marker specific for progenitor hematologic cancer cells. The present invention is also related to a method for diagnosing hematologic cancer.
Background of the Invention
Stem cells are commonly found in a variety of mammalian tissue systems. While the criteria by which such cells are defined vary depending upon the specific context, two properties are generally regarded as central features of stem cell populations: (1) stem cells must exhibit some capacity for self-replication or self-renewal, and (2) stem cells must be capable of differentiating into appropriate lineages (Potten C S: Stem Cells. London, Academic Press, 1997). Cells of this nature have been described for a number of tissues including hematopoietic, embryonic, neural, muscle and hepatic systems (Lemischka I R. Clonal, in vivo behavior of the totipotent hematopoietic stem cell. Semin Immunol 1991, 3: 349-55; Morrison S J, et al., The biology of hematopoietic stem cells. Annu. Rev. Cell Dev. Biol. 1995, 11: 35-71; Robertson E J., Using embryonic stem cells to introduce mutations into the mouse germ line. Biol Reprod 1991, 44: 238-45; Gage F H., Mammalian neural stem cells. Science 2000, 287: 1433-8; and, Alison M, et al., Hepatic stem cells. J Hepatol 1998, 29: 676-82). Thus, it is perhaps not surprising that similar cells have recently been documented in the context of malignant populations (Bonnet D, et al., Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 1997, 3: 730-737; Blair A, et al., Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(−)/HLA-DR-. Blood 1998, 92: 4325-35; Cobaleda C, et al., A primitive hematopoietic cell is the target for the leukemic transformation in human Philadelphia-positive acute lymphoblastic leukemia. Blood 2000, 95: 1007-13). Indeed, a stem cell is in some respects the ideal target for malignant transformation in that relatively little biological change is required. Since stem cells already possess the genetic programming necessary to be highly proliferative and developmentally plastic, one can imagine that relatively subtle perturbations might be sufficient to induce disease.
One example of neoplasia arising from malignant stem cells has recently been documented in the hematopoietic system in the case of acute myelogenous leukemia (AML). This disease is characterized by premature arrest of myeloid development and the subsequent accumulation of large numbers of non-functional leukemic blasts. While leukemic blast cells are often of clonal origin and display relatively homogeneous features, it has been demonstrated that such populations are organized in a hierarchical fashion, analogous to normal hematopoietic progenitors. Thus, there is a phenotypically defined leukemic stem cell population that is sufficient to propagate leukemic blasts both in vitro and in vivo in xenogeneic mouse models of human AML (Bonnet D, et al., Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 1997, 3: 730-737; Blair A, et al., Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(−)/HLA-DR-. Blood 1998, 92: 4325-35; Cobaleda C, et al., A primitive hematopoietic cell is the target for the leukemic transformation in human Philadelphia-positive acute lymphoblastic leukemia. Blood 2000, 95: 1007-13; Blair A, et al. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood 1997, 89: 3104-12). The concept of a leukemic stem cell (LSC) becomes critically important in considering the etiology of human disease. Clearly, in order to achieve durable remission, it will be necessary to specifically ablate the primitive or progenitor LSC population. However, previous studies (Terpstra W, et al., Fluorouracil selectively spares acute myeloid leukemia cells with long-term growth abilities in immunodeficient mice and in culture. Blood 1996, 88: 1944-50), as well as data from our group, suggest that LSC's are biologically distinct from more mature leukemic blasts and may not be responsive to conventional chemotherapeutic regimens. This observation is consistent with the clinical profile frequently seen for AML, wherein a majority of patients can achieve apparent complete remission, but in most cases will relapse (Schiller G J., Treatment of resistant disease. Leukemia 1998, 12 Suppl 1: S20-4; Paietta E., Classical multidrug resistance in acute myeloid leukemia. Med Oncol 1997, 14: 53-60). If LSC's are more refractile to chemotherapy than blasts, it is attractive to propose that surviving stem cells are a major contributing factor to leukemic relapse. Thus, strategies that specifically target progenitor leukemia cells may provide more effective treatment for leukemia patients. In 1997, Bonnet and Dick described the phenotype for LSC's as CD34+/CD38− (Bonnet D, et al., Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 1997, 3: 730-737). We report that the IL-3 receptor alpha chain (CD123) is highly expressed on leukemic but not normal CD34+/CD38− hematopoietic cells. In view of this state of the art, there is a need in the art to provide a diagnostic method for detecting leukemia at an early stage, as well as more effective methods of treating this disease.